Abstract 323: CHI3L1 secreting PMN-MDSCs promote IFN-γ signaling in triple negative breast cancer
Authors: Ukjin Kim, Rumela Chakrabarti
Journal: Cancer Research (2023)

Abstract BACKGROUND: Triple-negative breast cancer (TNBC) is highly malignant and has a poor prognosis because it lacks hormone therapy options. Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), a major component in tumor microenvironment are known to help the progression and metastasis of breast cancer by suppressing the immune action of T-cells against cancer cells. We previously reported that TNBC patients have more PMN-MDSCs. New exciting studies have uncovered CHI3L1, a novel secreted protein in PMN-MDSCs using mouse models. In this study, we purpose to analyze function of CHI3L1+ MDSCs on TNBC cells using mouse models and TNBC patient samples. DESIGN/METHODS: We analyzed CHI3L1 expression in breast cancer tissues from human and mouse and in human patient blood. Mouse TNBC cells were treated with recombinant CHI3L1 (rCHI3L1) and followed by clonogenic assay, wound healing assay, tumorsphere formation assay and bulk RNA-seq. The cells were also injected into mammary fat pad of Balb/c mice and tumor growth and lung metastasis was evaluated. CHI3L1-KO MDSCs were generated by CRIPR KO and TNBC cells were treated with conditioned media (CM) or co-cultured with CHI3L1-KO MDSCs to evaluate tumorigenicity. Mouse tissues was stained with antibodies for immune populations. IL13Rα2, receptor of CHI3L1 was silenced with shRNA and followed by rCHI3L1 treatment to analyze its involvement in PMN-MDSCs. RESULTS: We found that CHI3L1 expression was increased in stromal cells of TNBC patients and in stroma of TNBC mouse models. Among stromal cells, MDSCs have higher CHI3L1 levels than tumor-associated macrophages and cancer-associated fibroblasts, suggesting that MDSCs are major stromal component. Flow analysis of blood from breast cancer patients confirmed that TNBC patients have more PMN-MDSCs and CHI3L1+ PMN-MDSCs than non-TNBC patients. Interestingly, Afro-American TNBC tend to have higher CHI3L1+ PMN-MDSCs. Experimental data shows that rCHI3L1 increased proliferation and invasion of TNBC in vitro and in vivo. However, rCHI3L1 has no effect on non-TNBC cells, implying TNBC-specific function of CHI3L1. When CM from CHI3L1-KO MDSCs was given to TNBC, the TNBC growth was reduced. RNA-seq showed that CHI3L1 increased IFN-γ signaling in TNBC cells, which seems to be related to altered immune microenvironment including decreased CD8+ T cells and increased immunosuppressive Foxp3+ Treg cells in TNBC tissues. Silencing IL13Rα2 (receptor for CHI3L1) in TNBC cells hampered pro-tumorigenic functions of CHI3L1, reinforcing connection between CHI3L1 and IFN-γ signaling. CONCLUSION: Our results show TNBC patients have higher CHI3L1 secreting PMN-MDSCs, which induce tumor progression and metastasis with altered immune landscape via IL13Rα2 in TNBC, suggesting CHI3L1 as a potential target for suppressing the non-immunologic function of PMN-MDSCs in TNBC. Citation Format: Ukjin Kim, Rumela Chakrabarti. CHI3L1 secreting PMN-MDSCs promote IFN-γ signaling in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 323.